Linking abnormal mitosis to the acquisition of DNA damage

Abstract

Cellular defects that impair the fidelity of mitosis promote chromosome missegregation and aneuploidy. Increasing evidence reveals that errors in mitosis can also promote the direct and indirect acquisition of DNA damage and chromosome breaks. Consequently, deregulated cell division can devastate the integrity of the normal genome and unleash a variety of oncogenic stimuli that may promote transformation. Recent work has shed light on the mechanisms that link abnormal mitosis with the development of DNA damage, how cells respond to such affronts, and the potential impact on tumorigenesis.

microRNA-34a promotes DNA damage and mitotic catastrophe

“…34 During mitosis, 53BP1 and a number of γH2AX-dependent factors fail to localize on the condensed chromosomes and to form IRIF. 35,36 The aberrant mitotic progression results in accumulation of de novo DNA damage, which can be propagated to the next cell cycle but usually initiates permanent cell cycle arrest and cell death.…”

“…35,36 The aberrant mitotic progression results in accumulation of de novo DNA damage, which can be propagated to the next cell cycle but usually initiates permanent cell cycle arrest and cell death. 34,37 To explore the impact of miR-34a on mitosis, we examined microscopically asynchronous cells subjected to the low IR doses (1.3 Gy and 1 Gy for U87 and U251 cell lines, respectively) and related mitotic phases to the presence of 53BP1 IRIF. IR at low doses activates the G 2 /M checkpoint 7 and elicits various pathways of DNA repair response.…”

Neoplastic-Like CELL Changes of Normal Fibroblast Cells Associated with Evolutionary Conserved Maternal and Paternal Genomic Autonomous Behavior (Gonomery)

“…It is not known to what extent anaphase-A separate/weaken the cohesion between the 3 centromere regions of diplochromosomes (Figure 1(B)), especially in repeated endomitotic replication as discussed for Barrett' esophagus. But in either case the first meiotic-like (ML-1) division has probability of abnormal aneuploid chromosomal distribution, the whole chromosomal loss-type [44] that however, can be hidden by compensated uniparental disomy (UPD) [45]. These potentially, unstable divisions may also be associated with breakage [13] [14] with possibility for chromosomal rearrangements that can lead to segmental UPDs [46].…”

The shock of being united and symphiliosis

“…Tetraploidy is thought to cause cancer primarily by increasing the incidence of chromosomal aberrations that result from overloading the mitotic machinery with extra chromosomes and from enabling multipolar mitoses with extra centrosomes, 11,14,15,[19][20][21][22][23][24][25] although other consequences of having extra chromosomes, such as increased DNA damage, are also considered. 11,15,19,26 If doubling the number of chromosomes and centrosomes is indeed the primary oncogenic consequence of tetraploidy, then how cells become tetraploid, which can happen by endoreduplication, cytokinesis failure or cell fusion is irrelevant, as it has been tacitly assumed.…”

“…11,15,19,26 If doubling the number of chromosomes and centrosomes is indeed the primary oncogenic consequence of tetraploidy, then how cells become tetraploid, which can happen by endoreduplication, cytokinesis failure or cell fusion is irrelevant, as it has been tacitly assumed. 15,[19][20][21][22][23][24][25][26][27][28] If this assumption is correct, then the contribution of these three mechanisms to cancer and thus their potential as targets for cancer prevention is directly proportional to their incidence in the body. The role of polyploidy in plant evolution suggests that these assumptions may need to be reconsidered.…”